Investigating the role of LRRTM3 in Alzheimer’s disease: The characterisation of an LRRTM3 knock-out mouse model

The Leucine-rich repeat transmembrane neuronal 3 (LRRTM3) is a gene nested in the seventh intron of α-T catenin (CTNNA3). Genetic studies have demonstrated its association with Alzheimer’s disease (AD) and high plasma amyloid-β (Aβ) levels, making it an excellent positional and functional AD candidate gene, modulating risk through an Aβ pathway. Here, we characterise an LRRTM3 knock-out mouse model through behavioural phenotyping and qualitative immunohistochemistry (IHC) to ascertain the role of LRRTM3 in-vivo in a four-week-old cohort of mice. The rotarod test revealed significant motor deficits in the knock-outs which were exacerbated in males. Though the performance of heterozygotes and knock-outs improved over the course of the testing, only the heterozygotes overcame the deficit and the phenotype re-emerged on the final day in male knock-outs [Day 1: Males: F(2, 27) = 5.29, P = 0.012; Females: F(2, 24) = 5.51 ; P = 0.011; Day 2: Males: F(2, 27) = 6.76 ; P = 0.004; Females: F(2, 24) = 0.32 ; P = 0.733]. In the open field assay, elevated plus maze, social interaction, contextual and cued fear conditioning and Morris water maze tests, genotype did not significantly affect behavioural responses (P > 0.05). The IHC pathologically confirmed the absence of AD neuropathology, myelination defects in white matter tracts, astrocytic involvement, neuroinflammation and phosphorylated neurofilaments in the hippocampus and dorsal corticospinal tract. Collectively, these results indicate that LRRTM3 could potentially precipitate the motor deficits by modulating neurotransmitter release through its interactions with synaptic proteins or through the non-myelinating functions of oligodendrocytes.